The effect of unsaturated long-chain non-esterified fatty acids (NEFA) on the human leucocyte sodium-pump was studied in vivo. 2. Plasma NEFA level was raised acutely from 0.28 (SD 0.10) to 2.54 (SD 0.48) mmol/l by infusion of 'Intralipid 20%' (trademark) at 90 ml/h with heparin, and the human leucocyte 22Na efflux rate constants were studied in eight normal weight males. 3. After 3 h, there was a significant lowering of the total (from 3.97 (SD 0.92) to 3.10 (SD 0.71)/h; P less than 0.01) and ouabain-sensitive 22Na efflux rate constants (from 2.89 (SD 0.55) to 2.37 (SD 0.62)/h; P less than 0.02). Ouabain-insensitive efflux rate constants showed a tendency to fall (from 1.08 (SD 0.51) to 0.73 (SD 0.23)/h). Leucocyte potassium content remained unchanged, but sodium content rose from 31 (SD 12) to 38 (SD 18) mmol/kg dry weight (P less than 0.05). Total, ouabain-insensitive and ouabain-sensitive efflux rates did not change significantly during the Intralipid-heparin infusion. 4. Plasma insulin levels rose gradually throughout the 3 h infusion period. 5. In conclusion, NEFA, when raised to pathological levels, can inhibit the leucocyte Na-pump in vivo even in the presence of physiological levels of serum albumin, and may increase insulin secretion.